Definition/General
Introduction:
Vulvar adenosquamous carcinoma is a rare malignant tumor showing both glandular and squamous differentiation
Represents 2-5% of all vulvar malignancies
Defined as having ≥25% of each component (glandular and squamous)
Has aggressive behavior and poor prognosis compared to pure squamous cell carcinoma
Often arises from Bartholin glands or shows de novo mixed differentiation.
Origin:
Can arise from Bartholin glands with mixed differentiation
May originate from multipotent stem cells capable of dual differentiation
Collision tumor: separate adenocarcinoma and squamous cell carcinoma
Composite tumor: single tumor with mixed features
Metaplastic transformation of one component to another
HPV infection may play a role in some cases.
Classification:
Classified as primary vulvar adenosquamous carcinoma or metastatic from other sites
Bartholin gland origin (most common primary type)
Non-Bartholin origin
Collision type: two distinct tumors
Composite type: intimate mixture
HPV-related vs HPV-independent
Well-mixed vs poorly mixed variants.
Epidemiology:
Peak incidence in 5th-7th decades
Extremely rare tumor
Worse prognosis than pure squamous or adenocarcinoma
Higher tendency for recurrence
Earlier lymph node metastasis
Resistance to conventional therapy
Indian population data extremely limited due to rarity.
Clinical Features
Presentation:
Vulvar mass or ulcer
Rapid growth
Irregular, raised lesion
Bleeding (spontaneous or contact)
Pain and discomfort
Foul-smelling discharge
Pruritus
Early inguinal lymphadenopathy.
Symptoms:
Vulvar mass (85-95% cases)
Bleeding (70-80%)
Pain (60-70%)
Discharge (50-60%)
Pruritus (40-50%)
Dyspareunia
Urinary symptoms
Difficulty with personal hygiene
Rapid symptom progression.
Risk Factors:
Advanced age (>50 years)
HPV infection (types 16, 18)
Chronic vulvar inflammation
Lichen sclerosus
Immunosuppression
Smoking
Multiple sexual partners
Previous vulvar dysplasia
Radiation exposure.
Screening:
No specific screening protocol
High index of suspicion for complex vulvar lesions
Adequate biopsy essential for diagnosis
Multiple biopsies may be needed
Imaging for staging
Multidisciplinary team approach
Genetic counseling if familial.
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Gross Description
Appearance:
Large, irregular mass with mixed solid and cystic areas
Ulcerated surface with necrosis
Gray-white to tan coloration
Areas of keratinization (squamous component)
Mucoid areas (glandular component)
Hemorrhage and necrosis common.
Characteristics:
Heterogeneous appearance with varying consistency
Firm to hard areas (squamous)
Soft, mucoid areas (glandular)
Infiltrative borders
Surface ulceration
Calcifications may be present
Cystic degeneration possible.
Size Location:
Size ranges from 2-20 cm (typically large at presentation)
Most commonly posterolateral vulva (Bartholin gland area)
May involve multiple vulvar sites
Central vulvar location possible
Extension to adjacent structures common
Bilateral involvement rare.
Multifocality:
Usually unifocal but extensive
Local invasion into surrounding tissues
Early lymphatic spread
Satellite lesions may be present
Skip metastases to pelvic nodes
Hematogenous spread to distant organs.
Microscopic Description
Histological Features:
Intimate mixture of glandular and squamous elements
Glandular component: tubules, acini, mucin production
Squamous component: keratinization, intercellular bridges
Transition zones between components
High-grade nuclear atypia
Increased mitotic activity
Necrosis common.
Cellular Characteristics:
Pleomorphic cells with enlarged nuclei
Prominent nucleoli
Variable cytoplasm: eosinophilic (squamous) or clear/mucoid (glandular)
Mitotic figures abundant
Atypical mitoses
Multinucleated giant cells
Apoptotic bodies.
Architectural Patterns:
Composite pattern: intimate mixing of both components
Collision pattern: distinct areas of each component
Transition zones: gradual change from one to another
Infiltrative growth
Desmoplastic stroma
Lymphovascular invasion common
Perineural invasion.
Grading Criteria:
Grading based on both components
Predominant component grade
Overall architectural pattern
Nuclear pleomorphism
Mitotic rate
Necrosis extent
Most cases are high-grade
Well-differentiated variants extremely rare.
Immunohistochemistry
Positive Markers:
Glandular component: CK7+, CEA+, EMA+, mucin+
Squamous component: CK5/6+, p63+, CK14+
Both components: CK AE1/AE3+
p16 (variable, depends on HPV status)
p53 (often overexpressed)
Ki-67 (high proliferation index).
Negative Markers:
Site-specific markers (TTF-1, CDX2, PAX8 negative)
Neuroendocrine markers (chromogranin, synaptophysin negative)
Melanoma markers (S-100, HMB-45 negative)
Mesenchymal markers (vimentin, desmin negative)
Lymphoid markers (CD45 negative).
Diagnostic Utility:
Essential for confirming dual differentiation
CK7/CK5/6 dual positivity in different areas
p63 and CEA highlight respective components
p16 pattern suggests HPV association
Exclude metastatic disease with organ-specific markers
p53 pattern indicates mutation status.
Molecular Subtypes:
HPV-positive type: p16 diffuse positive, younger patients
HPV-negative type: p16 negative/patchy, older patients
p53-mutated type: aberrant p53 pattern
High-grade type: most common
Mixed hormone receptor status
Her2/neu variable.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60-80%)
PIK3CA mutations (30-40%)
KRAS mutations (20-30%)
HPV integration (subset of cases)
PTEN loss (20-30%)
CDKN2A deletions
EGFR amplification
BRCA1/2 mutations (rare).
Molecular Markers:
High tumor mutational burden
Chromosomal instability
p53 pathway disruption
PI3K/AKT pathway activation
MAPK pathway alterations
DNA repair defects
Angiogenesis markers elevated.
Prognostic Significance:
Worse prognosis than pure histological types
Higher recurrence rate
Earlier metastasis
Chemotherapy resistance
p53 mutations indicate aggressive behavior
HPV status may affect treatment response
Stage at diagnosis crucial.
Therapeutic Targets:
Multimodal therapy: surgery, radiation, chemotherapy
Platinum-based chemotherapy
Targeted therapy: EGFR inhibitors
Immunotherapy: checkpoint inhibitors
Anti-angiogenic therapy
Hormone therapy (if receptor positive)
Experimental protocols often needed.
Differential Diagnosis
Similar Entities:
Pure adenocarcinoma
Pure squamous cell carcinoma
Metastatic adenosquamous carcinoma
Collision tumor
Squamous cell carcinoma with mucin
Adenocarcinoma with squamous metaplasia
Poorly differentiated carcinoma.
Distinguishing Features:
Adenosquamous: ≥25% of each component, dual markers
Pure types: single lineage differentiation
Metastatic: organ-specific markers, clinical history
Collision: distinct, separate components
Quantitative assessment of components essential
Immunohistochemistry confirms dual differentiation.
Diagnostic Challenges:
Quantifying components accurately
Distinguishing from poorly differentiated carcinoma
Identifying minor components
Sampling adequacy crucial
Primary vs metastatic assessment
Grading mixed tumors
Multiple sections often needed.
Rare Variants:
Adenosquamous with neuroendocrine features
Adenosquamous with sarcomatoid features
Mucoepidermoid carcinoma
Adenosquamous with clear cell features
Pseudoglandular squamous cell carcinoma
Adenosquamous with sebaceous differentiation.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Vulvar excision from [site], measuring [size] cm
Diagnosis
Adenosquamous carcinoma
Classification and Components
Glandular component: [X]%, Squamous component: [X]%, Overall grade: [1/2/3]
Histological Features
Shows [intimate mixture/collision pattern] of [glandular] and [squamous] elements
Component Analysis
Glandular: [pattern and grade], Squamous: [pattern and grade]
Tumor Size
Tumor size: [X] cm in greatest dimension
Margins
Margins: [clear/involved], closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Special Studies
IHC: CK7: [result], CK5/6: [result], p63: [result], CEA: [result]
p16: [diffuse positive/negative/patchy]
[other study]: [result]
HPV Status
HPV status: [positive/negative/not determined]
Prognostic Factors
Risk factors: mixed histology, grade, size, stage, HPV status
Final Diagnosis
Vulvar adenosquamous carcinoma, [grade], [component percentages]